Study On Synthesis Of Phenylboronic-acid-Modified ε-polylysine-based Macromolecules,Preparation Of Their Glucose-responsive Particles And Microneedle Patches And Pronerties

The glucose-responsive phenylboronic-acid-based insulin-delivering systems are able to self-adaptively regulate the insulin-releasing rates according to blood glucose concentrations,which attract extensive attention in the field of diabetes treatments.The designing challenges of the phenylboronic-acid-based insulin-delivering systems lie in the realization of the excellent blood-glucose-controlling performance,good biosafety and simple preparation process.In this thesis,a series of glucose-responsive particles and microneedle patches were prepared based on the phenylboronic-acid-modified εpolylysine and its derivatives.And their insulin-loading properties,glucose-responsive insulin-releasing properties and the blood-glucose-controlling performances based on the diabetic rats were studied.(1)3 kinds of 4-carboxy-3-fluorophenylboronic-acid-modified ε-polylysine particles were prepared and the insulin-loading performances were studied based on the fluorescence-labeling method.The microneedle patch(GRP-MNP)was prepared by blending the insulin-loaded particle of the best insulin-loading performance(GRP)and pullulan.The in vitro insulin-releasing performances and the blood-glucose-controlling performances based on the diabetic rats of GRP and GRP-MNP were studied.The biosafety of the particle was studied.The result showed that the insulin-loading capacity of GRP was 0.113(g insulin/g particle).GRP had the glucose-responsive swelling performance and insulin-releasing performance.GRP endowed GRP-MNP with the glucose-responsive insulin-releasing performance.The microneedles of GRP-MNP were able to pierce the skin stratum corneum.GRP could control the blood glucose concentrations in the normal range and avoid the occurrence of hypoglycemia on the diabetic rats.GRP-MNP also had blood-glucose-controlling performances.The corresponding particle was of the low hemolysis ratio.And the organ trauma was unfound.The particle was of good biosafety.(2)9 kinds of fatty-acid/4-carboxyl-3-fluorophenylboronic-acid-modified εpolylysine particles were prepared.The insulin-loading performances and in vitro insulin-releasing performances of the particles were studied based on the fluorescencelabeling method.The self-assembly mechanism and glucose-responsive insulinreleasing mechanism of the particles were discussed.The blood-glucose-controlling performances of the insulin-loaded particles were studied based on the diabetic rats.The biosafety of the particles was studied.The result showed that the insulin-loading capacity of the C10PB particle,which possessed the best insulin-loading performance,was 0.171(g insulin/g particle).The C10PB particle had the glucose-responsive swelling performance and insulin-releasing performance.The insulin-loaded C10PB particle could control the blood glucose concentrations of diabetic rats in the normal range and avoid the occurrence of hypoglycemia.The C10PB particle was of the low cytotoxicity and low hemolysis ratio.And the organ trauma was unfound.The C10PB particle was of good biosafety.(3)17 kinds of modified ε-polylysine particles were prepared and the formulation with the best insulin-loading performance was screened out based on the fluorescencelabeling method.The microneedle patch was prepared based on the particle/polyvinylpyrrolidone-blending strategy.The in vitro insulin-releasing performances of the particle and microneedle patch were studied.The blood-glucose-controlling performances of the particle and microneedle patch were studied based on the diabetic rats.The biosafety of the particle and microneedle patch was studied.The result showed that the insulin-loading capacity of NAPB,the particle with the best insulin-loading performance,was 0.914(g insulin/g particle).NAPB had the glucose-responsive swelling performance and insulin-releasing performance.The NAPB-based microneedle patch(NA-MNP)also possessed the glucose-responsive insulin-releasing performance.The microneedles of NA-MNP were able to pierce the skin stratum corneum.Both NAPB and NA-MNP could control the blood glucose concentrations of diabetic rats in the normal range and avoid the occurrence of hypoglycemia.NA-MNP showed good blood-glucose-controlling performances on the diabetic rats under the three-meal-per-day-simulating condition.The carrier of NAPB was of the low cytotoxicity and low hemolysis ratio.And the organ trauma was unfound.Both NAPB and NA-MNP were of good biosafety.(4)6 kinds of insulin-loaded gel microneedle patches were prepared based on the 4-carboxy-3-fluorophenylboronic-acid-modified ε-polylysine/polyvinyl alcohol gels.The mechanical strengths,insulin-releasing performances,blood-glucose-controlling performances based on the diabetic rats and biosafety of the microneedle patches were investigated.The results showed that the microneedles were able to pierce the skin stratum corneum.The glucose-responsive insulin release of the microneedle patches were controlled by the phenylborate-ester-bond crosslinking points and the electrostatic interactions.GR-MNP,the microneedle patch with the best glucose-responsive insulinreleasing performance,showed good blood-glucose-controlling performances on the diabetic rats under the three-meal-per-day-simulating condition.The microneedle patch was of the low cytotoxicity and low hemolysis ratio.And the organ trauma was unfound.The microneedle patch was of good biosafety.